Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods

ABSTRACT

Compounds are provided having the formula (I)  
                 
wherein R, B, X and Y are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. ProvisionalApplication No. 60/640,110, filed Dec. 29, 2004, the disclosure of whichis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to pyrimidine-based inhibitors ofdipeptidyl peptidase IV (DPP-4), and to a method for treating multiplediseases or disorders by employing such pyrimidine -based inhibitorsalone, or in combination with another type of therapeutic agent.

BACKGROUND OF THE INVENTION

Dipeptidyl peptidase IV (DPP-4) is a membrane bound non-classical serineaminodipeptidase which is located in a variety of tissues (intestine,liver, lung, kidney) as well as on circulating T-lymphocytes (where theenzyme is known as CD-26). It is responsible for the metabolic cleavageof certain endogenous peptides (GLP-1(7-36), glucagon) in vivo and hasdemonstrated proteolytic activity against a variety of other peptides(GHRH, NPY, QLP-2, VIP) in vitro.

GLP-1(7-36) is a 29 amino-acid peptide derived by post-translationalprocessing of proglucagon in the small intestine. GLP-1(7-36) hasmultiple actions in vivo including the stimulation of insulin secretion,inhibition of glucagon secretion, the promotion of satiety, and theslowing of gastric emptying. Based on its physiological profile, theactions of GLP-1(7-36) are expected to be beneficial in the preventionand treatment of type II diabetes and potentially obesity. To supportthis claim, exogenous administration of GLP-1(7-36) (continuousinfusion) in diabetic patients has demonstrated efficacy in this patientpopulation. Unfortunately GLP-1(7-36) is degraded rapidly in vivo andhas been shown to have a short half-life in vivo (t½≈5 min). Based on astudy of genetically bred DPP-4 KO mice and on in vivo/in vitro studieswith selective DPP-4 inhibitors, DPP-4 has been shown to be the primarydegrading enzyme of GLP-1(7-36) in vivo. GLP-1(7-36) is degraded byDPP-4 efficiently to GLP-1(9-36), which has been speculated to act as aphysiological antagonist to GLP-1(7-36). Thus, inhibition of DPP-4 invivo should potentiate endogenous levels of GLP-1(7-36) and attenuateformation of its antagonist GLP-1(9-36) and thus serve to ameliorate thediabetic condition.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula (I) areprovided

wherein:

n=1 or 2;

R is a substitutent selected from the group consisting of hydrogen (H),halogen, cyano (CN), CF₃, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl,arylalkylthioalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, wherein anysuch substituent may optionally be substituted through available carbonatoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl,polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino,alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino,alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl,sulfonamido and sulfonyl;

B is selected from the group consisting of a bond, oxygen (O), nitrogen(N) and S(O)_(m);

m is 0, 1 or 2;

X is a substitutent selected from the group consisting of hydrogen (H),alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl,bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl andcycloheteroalkylalkyl, wherein any such substituent may optionally besubstituted through available carbon atoms with 1, 2, 3, 4 or 5 groupsselected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino,cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,cyano, amino, substituted amino, alkylamino, dialkylamino, thiol,alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;

B—X taken together can be a halogen; and

Y is aryl, optionally substituted with 1, 2, 3, 4 or 5 groups selectedfrom hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino,cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,cyano, amino, substituted amino, alkylamino, dialkylamino, thiol,alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl.

The definition of formula I above includes all pharmaceuticallyacceptable salts, stereoisomers, and prodrug esters of formula I.

The compounds of formula I possess activity as inhibitors of DPP-4 invivo and are useful in the treatment of diabetes and the micro- andmacrovascular complications of diabetes such as retinopathy, neuropathy,nephropathy, and wound healing. Such diseases and maladies are alsosometimes referred to as “diabetic complications”.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

Further provided is a method for treating or delaying the progression oronset of diabetes, especially type II diabetes, including complicationsof diabetes, including retinopathy, neuropathy, nephropathy and delayedwound healing, and related diseases such as insulin resistance (impairedglucose homeostasis), hyperglycemia, hyperinsulinemia, elevated bloodlevels of fatty acids or glycerol, obesity, hyperlipidemia includinghypertriglyceridemia, Syndrome X, atherosclerosis and hypertension, andfor increasing high density lipoprotein levels, wherein atherapeutically effective amount of a compound of formula I isadministered to a mammalian, e.g., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s) active in the therapeutic areas described herein.

In addition, a method is provided for treating diabetes and relateddiseases as defined above and hereinafter, wherein a therapeuticallyeffective amount of a combination of a compound of formula I and atleast one other type of therapeutic agent, such as an antidiabetic agentand/or a hypolipidemic agent, is administered to a human patient in needof treatment.

Further embodiments of the invention include compounds of formula Iwherein

n is 1, or compounds of formula I having the structure:

In the above method of the invention, the compound of formula (I) willbe employed in a weight ratio to the antidiabetic agent or other typetherapeutic agent (depending upon its mode of operation) within therange from about 0.01:1 to about 500:1, preferably from about 0.1:1 toabout 100:1, more preferably from about 0.2:1 to about 10:1.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I) may be generated by the methods as shown in thefollowing reaction schemes and the descriptions thereof.

Scheme 1 provides a general route to prepare aminomethylpyrimidines offormula (8). Acid chlorides of formula (2) may be obtained fromcommercial sources, or alternatively generated by methods as describedherein from the corresponding carboxylic acids of formula (1). Forexample, an acid chloride (2) can be formed by treating a carboxylicacid (1) with (COCl)₂ or SOCl₂ in an inert solvent such as methylenechloride or THF at 0 to 60° C. for 2-48 hours. Ketonitriles of formula(4) can be prepared by combining the lithium anion of acetonitrile withan acid chloride of formula (2). Acetonitrile (3) can be deprotonated bya strong base such as n-BuLi in an anhydrous solvent such as THF ordiethyl ether at low temperature to give the lithium anion ofacetonitrile. Acrylnitriles of formula (5) can be prepared by methodsknown to those skilled in the art such as heating ketonitrile of formula(4) with dimethylformamide dimethylacetal in an inert solvent such astoluene at elevated temperature for 2-48 hours. Amidines of formula (6)can either be obtained through commercial sources or convenientlyprepared by known methods. One example to make the amidines of formula(6) is to start with the corresponding nitrile, treating with HClfollowed by NH₃ to provide amidines (6). Pyrimidines of formula (7) canbe prepared by combining acrylonitriles (5) and amidines (6) by methodsknown in the art. For example, the process can be performed by heatingan acrylonitrile (5) and an amidine (6) with a base such as NaOMe inmethanol at room temperature to reflux for 2-48 hours.Aminomethylpyrimidines of formula (8) can be prepared from nitriles (7)through a reductive process. The reducing agents which may be used forthis process include, but are not limited to LAH, CoCl_(2/NaBH) ₄, RaneyNi/H₂, and Pd/H₂.

Scheme 2 describes an alternative route to prepareaminomethylpyrimidines of formula (8).

Ketoesters of formula (10) are known in the literature or can beconveniently prepared by known methods known. One example to prepareketoesters of formula (10) is to combine a ketone (9) with amethylcarbonate and a base such as NaH in an inert solvent such as THFat ambient temperature for 2-24 hours. Acryloesters of formula (11) canbe prepared by the same methods as described in Scheme 1 foracrylonitriles (5). Pyrimidine esters of formula (12) can be prepared bycombining an acryloester (11) and an amidine (6) using the same methodsas described in Scheme 1 for pyrimidines (7). Aminomethyl pyrimidines offormula (8) can then be prepared by those skilled in the art through areduction/oxidation sequence on pyrimidine esters of formula (12) asdescribed in scheme 2. The reducing agents that may be used to convertan ester of formula (12) to an alcohol of formula (13) include, but arenot limited to DIBAL, LAH, and Red-Al. The oxidizing agents that may beused to convert an alcohol of formula (13) to an aldehyde of formula(14) include, but are not limited to Dess-Martin periodinane, Swem, PCC,MnO₂, and TPAP/NMO. As understood by those skilled in the art, formula(15) can be either an oxime or an imine, which can be convenientlyprepared by combining an aldehyde of formula (14) with an amine orhydroxylamine. The reduction of compounds of formula (15) toaminomethylpyrimidines of formula (8) can be performed by using reducingagents such as Zn/HOAc, Pd/H₂, or Raney Ni/H₂.

Scheme 3 provides an alternative route of converting an alcohol offormula (13) to aminomethylpyrimidine of formula (8).

The chloropyrimidine of formula (16) can be formed from an alcohol offormula (13) by methods known to one skilled in the art. One example ofsuch a transformation is to treat an alcohol (13) with SOCl₂ in an inertsolvent such as CH₂Cl₂ at elevated temperature for 2-24 hours. Thechloropyrimidines of formula (16) can be converted toaminomethylpyrimidines of formula (8) by bubbling NH₃ gas to a solutionof chloropyrimidines (16) in a suitable solvent such as methanol.

Scheme 4 provides an alternative route for converting alcohols offormula (13) to aminomethylpyrimidines of formula (8).

An alcohol of formula (13) can be converted to a suitable leaving group,such as a mesylate, by treating the alcohol (13) with methanesulfonylchloride and a base such as triethylamine or pyridine in an inertsolvent such as tetrahydrofuran or methylene chloride at 0 to 60° C. for1 to 24 hours. The mesylates of formula (17) can then be converted toazides of formula (18) by known methods. One such set of conditionsinvolves treatment of a mesylate (17) with sodium azide in an inertsolvent such as DMF at room temperature to 100° C. for 1 to 24 hours.The azides of formula (18) can then be reduced to formaminomethylpyrimidines of formula (8). The reducing agents that may beused for this transformation include, but are not limited totriphenylphosphine, trialkylphosphine (including polymer supportedphosphines), lithium aluminum hydride, hydrogen with palladium, andplatinum containing catalysts.

Alkylated aminomethylpyrimidines of formula (19) can be prepared fromaldehydes of formula (14) as described in scheme 5. One example of sucha transformation can be found in: Hart, David J.; Kanai, Kenichi;Thomas, Dudley G.; Yang, Teng Kuei. Journal of Organic Chemistry (1983),48(3), 289-94. Another example of such a transformation is to add aGrignard reagent (R—MgBr) to the aldehyde, followed by oxidation,imine/oxime formation and reduction as described in Scheme 3.

Scheme 6 describes a route to prepare 6-substitutedaminomethylpyrimidines of formula (24).

Keto esters of formula (20) can either be obtained from commercialsources or conveniently prepared by the methods described in Scheme 2.Acryloesters of formula (22) can be prepared by known methods bycombining a ketoester of formula (20) and an aldehyde of formula (21).One example to prepare an acryloester of formula (22) is through aKnovenagel reaction. Pyrimidine esters of formula (23) can be preparedby methods known to those skilled in the art by combining acryloestersof formula (22) and amidines of formula (6) by known methods. Forexample, combining an acryloester of formula (22) and an amidine offormula (6) in the presence of a suitable base such as triethylamine,pyridine, NaOMe or KOAc in an inert solvent such as toluene, chloroform,benzene or DMF at elevated temperature gives pyrimidine esters offormula (23). The conversion of pyrimidine esters of formula (23) toaminomethylpyrimidines of formula (24) follows the same procedures asdescribed in Schemes 2, 3 and 4.

Scheme 7 describes an alternative route to prepareaminomethylpyrimidines of formula (8).

Pyrimidine esters of formula (25) can either be obtained throughcommercial sources or conveniently prepared by methods known in the art.The ester functionality of (25) can be converted to an alcohol offormula (26) by a reductive process. The reducing agents which may beused for this process include, but are not limited to LAH, DIBAL,Red-Al, and NaBH₄. The reaction can be performed by combining an ester(25) and the reducing agent in an inert solvent such as THF or tolueneat −78° C. to elevated temperature for 2-24 hours. Pyrimidine aldehydesof formula (27) can be prepared from pyrimidine alcohols of formula (26)by an oxidative process. The oxidizing agents which may be used for thisprocess include, but are not limited to PCC, Dess-Martin periodinane,Swern, and TPAP/NMO. The reaction can be performed in a solvent such asCH₂Cl₂, THF at −30° C. to ambient temperature for 2-24 hours.Pyrimidines of formula (29) can be prepared by combining achloropyrimidine of formula (27) and a boronic acid of formula (28) by aSuzuki coupling process. Boronic acids of formula (28) can be obtainedfrom commercial sources or conveniently prepared by methods known in theart. Examples of suitable palladium-catalyzed Suzuki coupling processcan be found in: Palladium reagents and catalysts: innovations inorganic synthesis, by Tsuji, Jiro; Palladium reagents in organicsyntheses by Richard F. Heck. The aminomethylpyrimidines of formula (8)can be synthesized from compounds of formula (29) according thechemistry described in Schemes 2, 3 and 4.

2-Amino-substituted pyrimidines of formula (x) can be prepared bymethods described in Scheme 8.

A ketoester of formula (22) can be condensed with an alkyl- orarylthioamidine such as (30) to give 2-alkylthiopyrimidines of formula(31) by known methods. One such set of conditions is to combine aketoester of formula (22) with an amidine of formula (30) in a suitablesolvent such as DMF at 20 to 100° C. for 1-72 hours. Molecular sievescan be added to facilitate the reaction. The alkylthio compound offormula (31) can be oxidized to an alkylsulfone of formula (32) by knownmethods. The oxidizing agents that may be used for this transformationinclude, but are not limited to mCPBA, hydrogen peroxide, PCC, and MnO₂.The alkylsulfone of formula (32) can then be displaced by amines to forma 2-aminosubstituted pyrimidine of formula (33). An example of one suchset of conditions which may be used for this conversion is to combine asulfone of formula (32) with a primary or secondary amine in a suitablesolvent such as methylene chloride, THF or DMF at rt to 100° C. for 1 to72 hours. The ester of formula (33) can be converted to anaminomethylpyrimidine of formula (34) by the same procedures asdescribed in Schemes 2, 3, and 4.

DEFINITIONS

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “alkyl” or “alk” as used hereinalone or as part of another group includes both branched andstraight-chain saturated aliphatic hydrocarbon radicals/groups havingthe specified number of carbon atoms. In particular, “Alkyl” refers to amonoradical branched or unbranched saturated hydrocarbon chain,preferably having from 1 to 40 carbon atoms, more preferably 1 to 10carbon atoms, even more preferably 1 to 6 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl,n-hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl, tetradecyl, andthe like, unless otherwise indicated. Unless otherwise constrained bythe definition for the alkyl substituent, such alkyl groups canoptionally be substituted with one or more substituents selected from amember of the group consisting of such as halo, alkyl, alkoxy, aryl,aryloxy, aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy,hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl,heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl,alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol,haloalkyl, trihaloalkyl and/or alkylthio.

Unless otherwise indicated, the term “cycloalkyl”, “carbocycle” or“carbocyclic” as employed herein alone or as part of another groupincludes saturated or partially unsaturated (containing 1 or 2 doublebonds) cyclic hydrocarbon groups containing 1 to 3 rings, includingmonocyclic alkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl,containing a total of 3 to 20 carbons forming the ring, preferably 3 to10 carbons, forming the ring and which may be fused to 1 or 2 aromaticrings as described for aryl, which includes, for example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyland cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 or moresubstituents such as of the substituents for described herein for alkylor aryl.

The term “Aryl” or “Ar” as used herein alone or as part of another grouprefers to an unsaturated aromatic carbocyclic group of from 5 to 20carbon atoms having a single ring (e.g., phenyl) or multiple condensed(fused) rings (e.g., naphthyl or anthryl). Representative examplesinclude, but are not limited to, aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless otherwiseconstrained by the definition for the aryl substituent, such aryl groupscan optionally be substituted with one or more substituents selectedfrom a member of the group consisting of hydrogen, halo, haloalkyl,alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, any of the alkyl substituents described herein, orsubstituted amino wherein the amino includes 1 or 2 substituents (whichare alkyl, aryl or any of the other aryl compounds mentioned in thedefinitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl,alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkyl-aminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,arylsulfinylalkyl, arylsulfonylamino or arylsulfon-aminocarbonyl and/orany of the alkyl substituents set out herein.

Unless otherwise indicated, the term “cycloheteroalkyl”, “heterocyclo”,“heterocyclic group” or “heterocyclyl” as used herein alone or as partof another group refers to a saturated or unsaturated group having asingle ring, multiple condensed rings or multiple covalently joinedrings, from 1 to 40 carbon atoms and from 1 to 10 hetero ring atoms,preferably I to 4 hetero ring atoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen. Preferably, “Heterocycle” or “Heterocyclicgroup” means a stable 5 to 7 membered monocyclic or bicyclic or 7 to 10membered bicyclic heterocyclic ring that may be saturated, partiallyunsaturated, or aromatic, and that comprises carbon atoms and from 1 to4 heteroatoms independently selected from a member of the groupconsisting of nitrogen, oxygen and sulfur and wherein the nitrogen andsulfur heteroatoms are optionally be oxidized and the nitrogenheteroatom may optionally be quaternized, and including any bicyclicgroup in which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic groups may be substituted on carbon or ona nitrogen, sulfur, phosphorus, and/or oxygen heteroatom, such as, butnot limited to, the substituents described for alkyl or aryl herein, solong as the resulting compound is stable. For example:

and the like.

“Heteroaryl” as used herein alone or as part of another group embracesunsaturated heterocyclic radicals. Examples of heteroaryl radicalsinclude unsaturated 3 to 6 membered heteromonocyclic group containing 1to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.)tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturatedcondensed heterocyclyl group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like. Further, examplesof heteroaryl groups include the following:

and the like. Unless otherwise constrained by the definition for theheteroaryl substituent, such heteroaryl groups can optionally besubstituted with one or more substituents, such as those described foralkyl or aryl herein.

Unless otherwise indicated, the term “alkenyl” as used herein alone oras part of another group refers to straight or branched chain radicalsof 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 1 to8 carbons in the normal chain, which include one to six double bonds inthe normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl,4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl,4,8,12-tetradecatrienyl, and the like. Optionally, said alkenyl groupmay be substituted with one or substituents, such as those substituentsdisclosed for alkyl.

Unless otherwise indicated, the term “alkynyl” as used herein alone oras part of another group refers to straight or branched chain radicalsof 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to8 carbons in the normal chain, which include one triple bond in thenormal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl,3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like.Optionally, said alkynyl group may be substituted with one orsubstituents, such as those substituents disclosed for alkyl.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup refers to partially unsaturated cyclic hydrocarbons containing 3to 12 carbons, preferably 5 to 10 carbons and 1 or 2 double bonds.Exemplary cycloalkenyl groups include cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, andcycloheptadienyl. Optionally, said cycloalkenyl group may be substitutedwith one or substituents, such as those substituents disclosed foralkyl.

The term “Bicycloalkyl” as employed herein alone or as part of anothergroup includes saturated bicyclic ring groups such as, withoutlimitation, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth.

The term “cycloalkenyl” as employed herein alone or as part of anothergroup includes partially unsaturated carbocyclic radicals having threeto twelve carbon atoms. Examples include, without limitation,cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “polycycloalkyl” as employed herein alone or as part of anothergroup includes two or more cycloalkyl ring systems, as defined herein,wherein at least one carbon atom is a part of at least two separatelyidentifiable ring systems. The polycycloalkyl group may contain bridgingbetween two carbon atoms, for example, bicyclo[1.1.0]butyl,bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricycl[2.2.1.0.sup.1]heptyl,norbornyl and pinanyl. The polycycloalkyl group may contain one or morefused ring systems, for example, decalinyl (radical from decalin) andperhydroanthracenyl. The polycycloalkyl group may contain a spiro union,in which a single atom is the only common member of two rings, forexample, spiro[3.4]octyl, spiro[3.3]heptyl and spiro[4.5]decyl.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine as well as CF₃.

The term “alkoxy” or “alkyloxy” as used herein alone or as part ofanother group, refers to an alkyl group, as defined herein, appended toa parent molecular moiety through an alkyl group, as defined herein.

The term ” haloalkoxy ” as used herein alone or as part of another grouprefers to alkoxy radicals, as defined herein, further substituted withone or more halo atoms, such as fluoro, chloro or bromo, to providehaloalkoxy radicals. Examples include, without limitation,fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoromethoxy,fluoroethoxy and fluoropropoxy.

The term “acyl” as employed herein by itself or part of another group,as defined herein, refers to an organic radical linked to a carbonyl

group; examples of acyl groups include a substituent group attached to acarbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl,cycloalkanoyl, cycloheteroalkanoyl and the like.

The term “cycloalkylalkyl”, “arylalkyl”, “cycloheteroalkyl”,“bicycloalkylalkyl” or “heteroarylalkyl” as used herein alone or as partof another group, refers to a cycloalkyl, an aryl, a cyclohetero, abicycloalkyl or heteroaryl group, as defined herein, appended to aparent molecular moiety through an alkyl group, as defined herein.Representative examples of arylalkyl include, but are not limited to,benzyl, 2-phenylethyl, 3-phenylpropyl, and the like.

The term “cycloheteroalkylalkyl” as used herein alone or as part ofanother group refers to a cycloheteroalkyl group as defined herein.linked through a C atom or heteroatom to a (CH₂)_(r) chain, where “r”can be 1 to 10.

The term “polyhaloalkyl” as used herein alone or as part of anothergroup refers to an “alkyl” group as defined above, having 2 to 9,preferably from 2 to 5, halo substituents, such as CF₃CH₂, CF₃ orCF₃CF₂CH₂.

The term “polyhaloalkoxy” as used herein refers to an “alkoxy” or“alkyloxy” group as defined above having 2 to 9, preferably from 2 to 5,halo substituents, such as CF₃CH₂O—, CF₃O— or CF₃CF₂CH₂O—.

The term “thiol” or “thio” as used herein alone or as part of anothergroup, refers to (—S) or (—S—).

The term “alkylthio” or “arylalkylthio” refers to an alkyl group or andarylalkyl group, as defined herein, linked to a parent molecular moietythrough a thiol group.

The term “alkylthioalkyl” or “arylalkylthioalkyl” refers to an alkylthiogroup or and arylalkylthio group, as defined herein, linked to a parentmolecular moiety through an alkyl group.

The term “hydroxy” as used herein alone or as part of another group,refers to a —OH group.

The term “hydroxyalkyl” as used herein alone or as part of anothergroup, refers to a hydroxyl group, as defined herein, appended to aparent molecular moiety through a alkyl group, as defined herein.

The term “cyano” as used herein alone or as part of another group,refers to a —CN group.

The term “nitro” as used herein, refers to a —NO₂ group.

The term “sulfinyl”, whether used alone or linked to other terms such asalkylsulfinyl, denotes respectively divalent radicals —S(O)—.

The term ” alkylsulfinyl ” as used herein alone or as part of anothergroup, refers to an alkyl group, as defined herein, appended to a parentmolecular moiety through a sulfinyl group, as defined herein.

The term “sulfonyl” as used herein alone or as part of another group,refers to an SO₂ group.

The term “alkylsulfonyl” or “aminosulfonyl”, as used herein, refer to analkyl or amino group, as defined herein, appended to a parent molecularmoiety through a sulfonyl group, as defined herein.

The term “amino” as employed herein, refers to an —NH₃ group or an aminelinkage: —NR_(a)—, wherein Ra may be as described below in thedefinition for “substituted amino”.

The term “substituted amino” as employed herein alone or as part ofanother group refers to amino substituted with one or two substituents.For example, NR_(a)R_(b), wherein R_(a) and R_(b) may be the same ordifferent and are, for example chosen from hydrogen, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, heterocyclic,arylalkyl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,cycloalkylalkyl, haloalklyl, hydrooxyalkyl, alkoxyalkyl or thioalkyl.These substituents may optionally be further substituted with any of thealkyl substituents as set out above. In addition, the amino substituentsmay be taken together with the nitrogen atom to which they are attachedto form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-lpiperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolindinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, triflouromethyl or hydroxyl.

The term “dialkylamino” as employed herein alone, or as part of anothergroup, refers to a substituted amino group having two alkylsubstituents. For example, NR_(a)R_(b), wherein R_(a) and R_(b) are eachan alkyl group, as defined herein.

The term “carbonyl” as used herein, refers to a —C(O)— group.

The term “aminocarbonyl”, “alkylcarbonyl”, “alkoxycarbonyl”,“arylcarbonyl”, “alkynylaminocarbonyl”, “alkylaminocarbonyl” and“alkenylaminocarbonyl” as used herein, refer to an amino group, alkylgroup, alkoxy group, aryl group, alkynylamino group, alkylamino group oran alkenylamino group, as defined herein, appended to a parent molecularmoiety through a carbonyl group, as defined herein.

The term “heteroarylamino”, “arylamino”, “alkylamino”,“alkylcarbonylamino”, “arylcarbonylamino”, “alkylsulfonylamino”,“alkylaminocarbonylamino” or “alkoxycarbonylamino” as used herein,refers to a heteroaryl, aryl, alkyl, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, alkylaminocarbonyl or alkoxycarbonyl group as definedherein, appended to a parent molecular moiety through an amino group, asdefined herein.

The term “sulfonamido” refers to —S(O)₂—NR_(a)R_(b), wherein Ra and Rbare as defined above for “substituted amino”.

The term “alkylcarbonyloxy” as used herein, refers to an “alkyl-CO—O—”group, wherein alkyl is as defined above.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includes,without limitation, instances where said event or circumstance occursand instances in which it does not. For example, optionally substitutedalkyl means that alkyl may or may not be substituted by those groupsenumerated in the definition of substituted alkyl.

“Substituted,” as used herein, whether express or implied and whetherpreceded by “optionally” or not, means that any one or more hydrogen onthe designated atom (C, N, etc.) is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.For instance, when a CH₂ is substituted by a keto substituent (═O), then2 hydrogens on the atom are replaced. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. Further, when more than one position in a givenstructure may be substituted with a substituent selected from aspecified group, the substituents may be either the same or different atevery position.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like.

Various forms of prodrugs are well known in the art. A comprehensivedescription of prodrugs and prodrug derivatives are described in:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch31, (Academic Press, 1996);

b) Design of prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds., Ch. 5, pgs 113-191 (Harwood Academic Publishers,1991). Said references are incorporated herein by reference.

The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, erectile dysfunction, and other known complications ofdiabetes.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, it is notuseful to specify an exact effective amount in advance.

The term “other type of therapeutic agents” as employed herein includes,but is not limited to one or more antidiabetic agents (other than DPP-IVinhibitors of formula I), one or more anti-obesity agents, one or moreanti-hypertensive agents, one or more anti-platelet agents, one or moreanti-atherosclerotic agents and/or one or more lipid-lowering agents(including anti-atherosclerosis agents).

UTILITIES AND COMBINATIONS

A. Utilities

The compounds of the present invention possess activity as inhibitors ofthe dipeptidyl peptidase IV which is found in a variety of tissues, suchas the intestine, liver, lung and kidney of mammals. Via the inhibitionof dipeptidyl peptidase IV in vivo, the compounds of the presentinvention possess the ability to potentiate endogenous levels ofGLP-1(7-36) and attenuate formation of its antagonist GLP-1(9-36).

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating ordelaying the progression or onset of diabetes(preferably Type II,impaired glucose tolerance, insulin resistance, and diabeticcomplications, such as nephropathy, retinopathy, neuropathy andcataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia,elevated blood levels of free fatty acids or glycerol, hyperlipidemia,hypertriglyceridemia, obesity, wound healing, tissue ischemia,atherosclerosis and hypertension. The compounds of the present inventionmay also be utilized to increase the blood levels of high densitylipoprotein (HDL).

In addition, the conditions, diseases, and maladies collectivelyreferenced to as “Syndrome X” or Metabolic Syndrome as detailed inJohannsson, J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may betreated employing the compounds of the invention.

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

Other “therapeutic agent(s)” suitable for combination with the compoundof the present invention include, but are not limited to, knowntherapeutic agents useful in the treatment of the aforementioneddisorders including: anti-diabetic agents; anti-hyperglycemic agents;hypolipidemic/lipid lowering agents; anti-obesity agents;anti-hypertensive agents, and appetite suppressants. Additionaltherapeutic agents suitable for combination with the compound of thepresent invention include agents for treating infertility, agents fortreating polycystic ovary syndrome, agents for treating a growthdisorder and/or frailty, an anti-arthritis agent, agents for preventinginhibiting allograft rejection in transplantation, agents for treatingautoimmune disease, an anti-AIDS agent, agents for treating inflammatorybowel disease/syndrome, agents for treating anorexia nervosa and ananti-osteoporosis agent.

Examples of suitable anti-diabetic agents for use in combination withthe compound of the present invention include biguanides (e.g.,metformin or phenformin), glucosidase inhibitors (e.g., acarbose ormiglitol), insulins (including insulin secretagogues or insulinsensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g.,glimepiride, glyburide, gliclazide, chlorpropamide and glipizide),biguanide/glyburide combinations (e.g., Glucovance®), thiazolidinediones(e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alphaagonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogenphosphorylase inhibitors, inhibitors of fatty acid binding protein(aP2), glucagon-like peptide-1 (GLP-1) or other agonists of the GLP-1receptor, STLT2 inhibitors and other dipeptidyl peptidase IV (DPP4)inhibitors.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570,englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Examples of PPAR-alpha agonists, PPAR-gamma agonists and PPARalpha/gamma dual agonists include muraglitizar, peliglitazar, AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), GW-501516 (Glaxo-Wellcome),KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, “ANovel Insulin Sensitizer Acts As a Coligand for PeroxisomeProliferation—Activated Receptor Alpha (PPAR alpha) and PPAR gamma.Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver ofZucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), WO 01/21602 and inU.S. Pat. No. 6,653,314, the disclosure of which is incorporated hereinby reference, employing dosages as set out therein, which compoundsdesignated as preferred are preferred for use herein.

Suitable aP2 inhibitors include those disclosed in U.S. application Ser.No. 09/391,053, filed Sep. 7, 1999, and in U.S. application Ser. No.09/519,079, filed Mar. 6, 2000, employing dosages as set out herein.

Suitable other DPP4 inhibitors include saxagliptin, those disclosed inWO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) as disclosed by Hughes et al, Biochemistry, 38(36),11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540),2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No.22, pp 1163-1166 and2745-2748 (1996), the compounds disclosed in U.S. application Ser. No.10/899641, WO 01/868603 and U.S. Pat. No. 6,395,767, employing dosagesas set out in the above references.

Other suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of suitable anti-hyperglycemic agents for use in combinationwith the compound of the present invention include glucagon-likepeptide-1 (GLP-1,) such as GLP-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492), as well asexenatide (Amylin/Lilly), LY-315902 (Lilly), MK-0431 (Merck),liraglutide (NovoNordisk), ZP-10 (Zealand Pharmaceuticals A/S), CJC-1131(Conjuchem Inc), and the compounds disclosed in WO 03/033671.

Examples of suitable hypolipidemic/lipid lowering agents for use incombination with the compound of the present invention include one ormore MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidco-transporter inhibitors, up-regulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein (e.g., CETPinhibitors, such as CP-529414 (Pfizer) and JTT-705 (Akros Pharma)), PPARagonists (as described above) and/or nicotinic acid and derivativesthereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat.No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S.Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compound of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930, visastatin (Shionogi-Astra/Zeneca(ZD-4522)), as disclosed in U.S. Pat. No. 5,260,440, and related statincompounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs ofmevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives, as disclosed in PCTapplication WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone, as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives, as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin), as disclosed inEuropean Patent Application No.0142146 A2, and quinoline and pyridinederivatives, as disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase, such as those disclosed in GB 2205837, are suitable for usein combination with the compound of the present invention.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al., J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates, as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

The fibric acid derivatives which may be employed in combination thecompound of formula I include fenofibrate, gemfibrozil, clofibrate,bezafibrate, ciprofibrate, clinofibrate and the like, probucol, andrelated compounds, as disclosed in U.S. Pat. No. 3,674,836, probucol andgemfibrozil being preferred, bile acid sequestrants, such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®),as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substitutedethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid, acipimox, acifran,neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine)derivatives, such as disclosed in U.S. Pat. No. 4,759,923, quaternaryamine poly(diallyldimethylammonium chloride) and ionenes, such asdisclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterollowering agents.

The ACAT inhibitor which may be employed in combination the compound offormula I include those disclosed in Drugs of the Future 24, 9-15(1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effective in theprevention and regression of aortic fatty streak area in hamsters”,Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85;“The pharmacological profile of FCE 27677: a novel ACAT inhibitor withpotent hypolipidemic activity mediated by selective suppression of thehepatic secretion of ApoB 100-containing lipoprotein”, Ghiselli,Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP 73163: abioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C.,et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co.Ltd).

The hypolipidemic agent may be an up-regulator of LD2 receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitor for use incombination with the compound of the invention include SCH48461(Schering-Plough), as well as those disclosed in Atherosclerosis 115,45-63 (1995) and J. Med. Chem. 41, 973 (1998).

Examples of suitable ileal Na+/bile acid co-transporter inhibitors foruse in combination with the compound of the invention include compoundsas disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination thecompound of formula I include 15-lipoxygenase (15-LO) inhibitors, suchas benzimidazole derivatives, as disclosed in WO 97/12615, 15-LOinhibitors, as disclosed in WO 97/12613, isothiazolones, as disclosed inWO 96/38144, and 15-LO inhibitors, as disclosed by Sendobry et al“Attenuation of diet-induced atherosclerosis in rabbits with a highlyselective 15-lipoxygenase inhibitor lacking significant antioxidantproperties”, Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelliet al, “15-Lipoxygenase and its Inhibition: A Novel Therapeutic Targetfor Vascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

Examples of suitable anti-hypertensive agents for use in combinationwith the compound of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompound of the present invention include a beta 3 adrenergic agonist, alipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, athyroid receptor beta drug, 5HT2C agonists, (such as Arena APD-356);MCHR1 antagonists such as Synaptic SNAP-7941 and Takeda T-226926,melanocortin receptor (MC4R) agonists, melanin-concentrating hormonereceptor (MCHR) antagonists (such as Synaptic SNAP-7941 and TakedaT-226926), galanin receptor modulators, orexin antagonists, CCKagonists, NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators,corticotropin releasing factor agonists, histamine receptor-3 (H3)modulators, 11-beta-HSD-1 inhibitors, adinopectin receptor modulators,monoamine reuptake inhibitors or releasing agents, a ciliaryneurotrophic factor (CNTF, such as AXOKINE® by Regeneron), BDNF(brain-derived neurotrophic factor), leptin and leptin receptormodulators, cannabinoid-1 receptor antagonists (such as SR-141716(Sanofi) or SLV-319 (Solvay)), and/or an anorectic agent.

The beta 3 adrenergic agonists which may be optionally employed incombination with compound of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064.

Examples of lipase inhibitors which may be optionally employed incombination with compound of the present invention include orlistat orATL-962 (Alizyme).

The serotonin (and dopoamine) reuptake inhibitor (or serotonin receptoragonists) which may be optionally employed in combination with acompound of the present invention may be BVT-933 (Biovitrum),sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron).

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with the compound of the present inventioninclude thyroid receptor ligands, such as those disclosed in WO97/21993(U. Cal SF), WO99/00353 (KaroBio) and GB98/284425 (KaroBio).

The monoamine reuptake inhibitors which may be optionally employed incombination with compound of the present invention include fenfluramine,dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline,chlorphentermine, cloforex, clortermine, picilorex, sibutramine,dexamphetamine, phentermine, phenylpropanolamine or mazindol.

The anorectic agent which may be optionally employed in combination withthe compound of the present invention include topiramate (Johnson &Johnson), dexamphetamine, phentermine, phenylpropanolamine or mazindol.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compound of the present invention may be used, for example, in thoseamounts indicated in the Physician's Desk Reference, as in the patentsset out above or as otherwise determined by one of ordinary skill in theart.

Where the compound of the invention are utilized in combination with oneor more other therapeutic agent(s), either concurrently or sequentially,the following combination ratios and dosage ranges are preferred.

Where the other antidiabetic agent is a biguanide, the compound offormula I will be employed in a weight ratio to biguanide within therange from about 0.01:1 to about 100:1, preferably from about 0.1:1 toabout 5:1.

The compound of formula I will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.5:1 to about 50:1.

The compound of formula I will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.2:1 to about 10:1.

The compound of formula I will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.2:1 to about 10:1.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Optionally, the sulfonyl urea and thiazolidinedione may be incorporatedin a single tablet with the compound of formula I in amounts of lessthan about 150 mg.

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and5,631,224 which are incorporated herein by reference.

The compound of formula I will be employed in a weight ratio to themeglitinide, PPAR-gamma agonist, PPAR-alpha/gamma dual agonist, aP2inhibitor or other DPP4 inhibitor within the range from about 0.01:1 toabout 100:1, preferably from about 0.2:1 to about 10:1.

The compound of formula I of the invention will be generally be employedin a weight ratio to the hypolipidemic agent (were present), within therange from about 500:1 to about 1:500, preferably from about 100:1 toabout 1:100.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg/kgto about 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor in an amount within the range of fromabout 1 to 2000 mg, and preferably from about 4 to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 5 to about 80 mg, and more preferably fromabout 10 to about 40 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The compound of the formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out a preferred method of the invention for treating any ofthe diseases disclosed herein, such as diabetes and related diseases, apharmaceutical composition will be employed containing one or more ofthe compound of formula I, with or without other antidiabetic agent(s)and/or antihyperlipidemic agent(s) and/or other type therapeutic agentsin association with a pharmaceutical vehicle or diluent. Thepharmaceutical composition can be formulated employing conventionalsolid or liquid vehicles or diluents and pharmaceutical additives of atype appropriate to the mode of desired administration, such aspharmaceutically acceptable carriers, excipients, binders and the like.The compound can be administered to mammalian species including humans,monkeys, dogs, etc. by an oral route, for example, in the form oftablets, capsules, beads, granules or powders, or they can beadministered by a parenteral route in the form of injectablepreparations, or they can be administered intranasally or in transdermalpatches. Typical solid formulations will contain from about 10 to about500 mg of a compound of formula I. The dose for adults is preferablybetween 10 and 2,000 mg per day, which can be administered in a singledose or in the form of individual doses from 1-4 times per day.

A typical injectable preparation may be produced by aseptically placing250 mg of compound of formula I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

It will be understood that the specific dose level and frequency ofdosage for any particular subject can be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the species, age, body weight, general health, sex and diet of thesubject, the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

DPP-4 inhibitory activity of the compounds of the present invention maybe determined by use of an in vitro assay system which measures thedegree in inhibition of DPP-4-mediated cleavage of an appropriatesubstrate or pseudo-substrate. Inhibition constants (Ki values) for theDPP-4 inhibitors of the invention may be determined by the methoddescribed in the experimental section below.

Cloning, Expression and Purification of Human DPP-4

To generate human DPP-4, PCR (Red-tag polymerase, Sigma) was performedon Human cDNA from placenta (Clontech) using two primers,ACGCCGACGATGAAGACA and AGGTAAAGAGAAACATTGTT, based on the nucleotidesequence of the human clone (accession number M74777). PCR products werecloned into the pcDN4/HisMax TOPO vector (Invitrogene). For stabletransfection of CHO-DG44 cells, DPP4 was rePCRed using primersGGTACCAGCGCAGAGGCTT and CTCGAGCTAAGGTAAAGAGAAACATTG to generate KpnI andXhoI sites. The KpnI and XhoI sites were used to extract the N-terminalHis tagged gene. The His tag, which could be cleaved and removed byEnterokinase, was included to allow purification using the TALONaffinity column. The gene was then ligated into the KpnI and XhoI sitesof the pD16 vector for stable transfection. Stable cell lines weregenerated by transfecting the expression vector into Chinese hamsterovary (CHO-DG44) cells using electroporation. The CHO-DG44 cell line wasgrown in PFCHO media supplemented with HT (glycine, hypoxanthine andthymidine, Invitrogene), glutamine and Recombulin (ICN). Then 1×10⁷cells/ml were collected, transfected with 60 μg of DNA usingelectroporation at 300V, and then transferred to a T75 flask. On thethird day following transfection, the HT supplement was removed andselection was initiated with methotrexate (MTX, 10 nM, ICN). After afurther 10 days the cells were plated into individual wells of 96 wellplates. Every 10 days the concentration of MTX was increased two tothree fold, up to a maximum of 400 nM. Final stable cell line selectionwas based on yield and activity of the expressed protein.

An attempt to purify recombinant DPP-4 using Talon resin was notefficient, resulting in small yields, with most of the DPP activitypassing through the column. Therefore, protein was further purifiedusing conventional anion exchange (Sepharose Q), gel filtration (S-200)and high resolution MonoQ columns. The final protein yielded a singleband on SDS-PAGE gels. Amino acid sequence analysis indicated twopopulations of DPP-4 in the sample. One portion of the protein had 27amino acids truncated from the N-terminus, while the other was lackingthe N-terminal 37 amino acids. This suggests that during isolation theentire transmembrane domain (including His tag) is removed by proteasespresent in the CHO cells. Total protein concentration was measured usingthe Bradford dye method and the amount of the active DPP-4 wasdetermined by titrating the enzyme with a previously characterizedinhibitor (Ki=0.4 nM). No biphasic behavior was observed duringinhibition or catalysis, suggesting that both protein populations arefunctionally identical.

DPP-4 Inhibition Assays.

Inhibition of human DPP-4 activity was measured under steady-stateconditions by following the absorbance increase at 405 nm upon thecleavage of the pseudosubstrate, Gly-Pro-pNA. Assays were performed in96-well plates using a Thermomax plate reader. Typically reactionscontained 100 μl of ATE buffer (100 mM Aces, 52 mM Tris, 52 mMethanolamine, pH 7.4), 0.45 nM enzyme, either 120 or 1000 μM ofsubstrate (S<Km and S>Km, Km=180 μM) and variable concentration of theinhibitor. To ensure steady-state conditions for slow-bindinginhibitors, enzyme was preincubated with the compound for 40 minutesprior to substrate addition, to initiate the reaction. All serialinhibitor dilutions were in DMSO and final solvent concentration did notexceed 1%.

Inhibitor potency was evaluated by fitting inhibition data to thebinding isotherm: $\begin{matrix}{\frac{vi}{v} = {\frac{Range}{1 + \left( \frac{I}{{IC}_{50}} \right)^{n}} + {Background}}} & (1)\end{matrix}$where vi is the initial reaction velocity at different concentrations ofinhibitor I; v is the control velocity in the absence of inhibitor,range is the difference between the uninhibited velocity and background;background is the rate of spontaneous substrate hydrolysis in the absentof enzyme, n is the Hill coefficient.

Calculated IC₅₀ at each substrate concentration were converted to Kiassuming competitive inhibition according to: $\begin{matrix}{{Ki} = \frac{{IC}_{50}}{\left( {1 + \frac{S}{Km}} \right)}} & (2)\end{matrix}$

All inhibitors were competitive as judged by a very good agreement of Kivalues obtained from the assays at high and low substrateconcentrations. In cases where IC₅₀ at the low substrate concentrationwas close to the enzyme concentration used in the assay, the data werefit to the Morrison equation¹, to account for the depletion of the freeinhibitor:¹Morrison, J F, Walsh, C T. Advances in Enzymology. 61 (1988), 201-206.$\begin{matrix}{\frac{vi}{v\quad 0} = {1 - \frac{\left( {E + I + {IC}_{50}} \right) - \sqrt{\left( {E + I + {IC}_{50}} \right)^{2} - {4{EI}}}}{2E}}} & (3)\end{matrix}$where vi and vo are the steady state velocities measured in the presenceand absence of inhibitor, E enzyme concentration.

Each IC₅₀ was further refined to Ki, to account for the substrateconcentration in the assay using equation (2).

ABBREVIATIONS

The following abbreviations are employed in the Examples and elsewhereherein:

-   Ph=phenyl-   Bn=benzyl-   i-Bu=iso-butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Bu=butyl-   TMS=trimethylsilyl-   FMOC=fluorenylmethoxycarbonyl-   Boc or BOC=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   HOAc or AcOH=acetic acid-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   EtOAc=ethyl acetate-   THF=tetrahydrofuran-   TFA=trifluoroacetic acid-   Et₂NH=diethylamine-   NMM=N-methyl morpholine-   n-BuLi=n-butyllithium-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   TEA=triethylamine-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=mole(s)-   mmol=millimole(s)-   meq=milliequivalent-   rt=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   t_(R)=retention time-   mp=melting point-   HPLC=high performance liquid chromatography-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   EDCI or EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide    hydrochloride (or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide    hydrochloride)-   HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate-   HOAT=1-hydroxy-7-azabenzotriazole-   PyBOP reagent=benzotriazol-1-yloxy-tripyrrolidino phosphonium    hexafluorophosphate-   equiv=equivalent(s)-   UCT=United Chemical Technologies, Inc.; Bristol, Pa.

EXAMPLES

The following examples are provided to describe the invention in furtherdetail. These examples, which set forth the best mode presentlycontemplated for carrying out the invention, are intended to illustrateand not to limit the invention.

In general, preferred compounds of the present invention, such as thecompounds disclosed in the following examples, have been identified toinhibit the catalytic activity of dipeptidyl peptidase IV atconcentrations equivalent to, or more potently than, 10 μM, preferably 5μM, more preferably 3 μM, thereby corroborating the utility of thecompounds of the present invention as effective inhibitors dipeptidylpeptidase IV. Potencies can be calculated and expressed as eitherinhibition constants (Ki values) or as IC50 (inhibitory concentration50%) values, and refer to activity measured employing the in vitro assaysystem described herein.

Example 1

Example 1 Step 1. 3-(2,4-Dichlorophenyl)-3-oxopropanenitrile

To a stirred solution of acetonitrile (2.0 mL, 38.2 mmol) in THF (50 mL)at −78° C. was added ^(n)BuLi (1.81 M in hexane, 16 mL, 28.7 mmol). Theresulting slurry was kept at −78° C. for 15 min and 2,4-dichlorobenzoylchloride (2.0 g, 9.55 mmol) was added dropwise to the acetonitrileanion. After 40 min, the reaction was quenched by addition of saturatedNH₄Cl (30 mL). THF was removed under reduced pressure and the suspensionwas filtered. The solid was washed with H₂O (100 mL) and dried to give3-(2,4-dichlorophenyl)-3-oxopropanenitrile (2.0 g, 98%, >95% purity) asa light yellow solid.

¹H NMR (400 MHz, CDCl₃) 7.64 (d, J=8.32 Hz, 1H), 7.52 (d, J=1.76 Hz,1H), 7.41 (dd, J=1.76, 8.32 Hz, 1H), 4.13 (s, 2H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=2.73 min, 95.5%homogeneity index.

LCMS: Anal. Calcd. for C₉H₅Cl₂NO 212.97 found: 211.89 (M−H)⁻.

Example 1 Step 2. 2-(2,4-Dichlorobenzoyl)-3-(dimethylamino)acrylonitrile

To a stirred solution of step 1 nitrile (1.74 g, 8.13 mmol) in toluene(50 mL) was added dimethylformamide dimethylacetal (1.35 mL, 10.16mmol). The resulting brown solution was heated to 50° C. for 1 hr. Thesolvent was removed under reduced pressure and the residue was dilutedwith CH₂Cl₂ (50 mL). The organic layer was washed with saturated NaHCO₃solution (50 mL) and brine (50 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure to give the crude product as a brownoil. Purification of the crude product by flash chromatography (silicagel, 40% EtOAc/hexane) afforded2-(2,4-dichlorobenzoyl)-3-(dimethylamino)acrylonitrile (1.5 g, 69%) as alight brown oil.

¹H NMR (400 MHz, CDCl₃) 7.43 (s, 1H), 7.30 (s, 2H), 3.48 (s, 3H), 3.32(s, 3H).

Example 1 Step 3.4-(2,4-Dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidine-5-carbonitrile

To a stirred solution of Step 2 acrylonitrile (1.5 g, 5.6 mmol) and3,5-dimethoxybenzamidine hydrochloride (1.2 g, 5.6 mmol) in MeOH (30 mL)was added NaOMe (25% in MeOH, 2.56 mL, 11.2 mmol). The reaction washeated to reflux for 5 hr. Additional NaOMe (25% in MeOH, 2.56 mL, 11.2mmol) was added and was kept for 16 hr. The reaction was cooled toambient temperature and quenched by addition of H₂O (50 mL). Thereaction was filtered and the solid was washed with MeOH (40 mL) to give4-(2,4-dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidine-5-carbonitrile(960 mg, 38.4%) as a white solid.

¹H NMR (400 MHz, CDCl₃) 9.10 (s, 1H), 7.71 (d, J=2.2 Hz, 2H), 7.62 (d,J=1.75 Hz, 1H), 7.51 (d, J=7.78 Hz, 1H), 7.47 (dd, J=1.75, 7.76 Hz, 1H),6.68 (t, J=2.1 Hz, 1H), 3.88 (s, 6H).

¹³H NMR (400 MHz, CDCl₃) 166.44, 165.67, 161.25, 160.79, 137.63, 137.59,133.62, 133.31, 131.66, 130.49, 127.71, 114.93, 107.07, 106.89, 105.64,55.65.

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=4.14 min.

LCMS: Anal. Calcd. for C₁₉H₁₃C₁₂N₃O₂ 385.04 found: 386.15 (M+H)⁺.

Example 1 Step 4.(4-(2,4-Dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-5-yl)methanamine

To a stirred solution of Step 3 carbonitrile (35 mg, 0.09 mmol) in THF(2 mL) and H₂O (1 mL) was added CoCl₂.6H₂O (20 mg, 0.09 mmol) followedby NaBH₄ (17 mg, 0.45 mmol) in H₂O (0.5 mL). A black precipitate formedimmediately with gas evolution. After 30 min, the reaction was filteredand diluted with CH₂Cl₂ (6 mL). The organic layer was washed withsaturated NaHCO₃ solution (5 mL) and brine (5 mL), dried (MgSO₄),filtered and concentrated under reduced pressure to give the crudeproduct as a yellow oil. Purification of the crude product byreverse-phase preparative HPLC provided(4-(2,4-dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-5-yl)methanamine,TFA salt (20 mg, 44%) as a light yellow solid.

¹H NMR (400 MHz, CD₃OD) 9.06 (s, 1H), 7.41 (s, 1H), 7.64 (d, J=2.64 Hz,2H), 7.61 (dd, J=1.76, 7.75 Hz, 1H), 7.55 (d, J=7.76 Hz, 1H), 6.66 (d,J=1.80 Hz, 1H), 4.02 (br s, 2H), 3.84 (s, 6H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.1% trifluoroacetic acid,B=10% water, 90% methanol, 0.1% trifluoroacetic acid, RT=3.19 min, 97%homogeneity index.

HRMS: Anal. Calcd. for C₁₉H₁₇C₁₂N₃O₂ 390.0776 found: 390.0778 (M+H)⁺.

Example 2

(4-(2,4-Dichlorophenyl)-2-phenylpyrimidin-5-yl)methanamine, TFA salt wasprepared by the methods described in Example 1, Step 3 and Step 4 usingExample 1, Step 2 acrylonitrile and benzamidine hydrochloride.

¹H NMR (400 MHz, CD₃OD) 9.07 (s, 1H), 8.46 (dd, J=1.76, 8.36 Hz, 2H),7.76 (d, J=1.44 Hz, 1H), 7.47-7.63 (m, 5H), 4.16 (br s, 2H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=2.82 min, 98%homogeneity index.

LCMS: Anal. Calcd. for C₁₇H₁₃C₁₂N₃ 329.05 found: 330.14 (M+H)⁺.

Example 3

(4-(2,4-Dimethylphenyl)-2-methylpyrimidin-5-yl)methanamine, TFA salt wasprepared by the methods described in Example 1, using2,4-dimethylbenzaldehyde for Step 1 and acetamidine for Step 3.

¹H NMR (400 MHz, CD₃OD) 8.79 (s, 1H), 7.13 (s, 1H), 7.06 (d, J=8.8 Hz,1H), 7.03 (d, J=8.8 Hz, 1H), 3.91 (s, 2H), 2.63 (s, 3H), 2.27 (s, 3H),2.00 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=2.64 min, 95%homogeneity index.

HRMS: Anal. Calcd. for C₁₄H₁₇N₃ 228.1501 found: 228.1491 (M+H)⁺.

Example 4

(4-(4-Chlorophenyl)-2-phenylpyrimidin-5-yl)methanamine, TFA salt wasprepared by the methods described in Example 1 using 4-chlorobenzoylchloride for Step 1 and benzamidine hydrochloride for Step 3.

¹H NMR (400 MHz, CD₃OD) 8.93 (s, 1H), 8.40 (dd, J=1.76, 7.88 Hz, 2H),7.63 (d, J=8.32 Hz, 2H), 7.52 (d, J=8.80 Hz, 2H), 7.42 (m, 1H), 7.41 (d,J=7.04 Hz, 2H), 4.26 (s, 2H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=5.05 min, 96%homogeneity index.

HRMS: Anal. Calcd. for C₁₇H₁₅ClN₃ 296.0955 found: 296.0947 (M+H)⁺.

Example 5

(4-(2-Chlorophenyl)-2-phenylpyrimidin-5-yl)methanamine, TFA salt wasprepared by the methods described in Example 1 using 2-chlorobenzoylchloride for Step 1 and benzamidine hydrochloride for Step 3.

¹H NMR (400 MHz, CD₃OD) 9.08 (s, 1H), 8.47 (dd, J=1.32, 7.48 Hz, 2H),7.47-7.67 (m, 7H), 4.01 (br s, 2H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=4.92 min, 95%homogeneity index.

HRMS: Anal. Calcd. for C₁₇H₁₅ClN₃ 296.0955 found: 296.0945 (M+H)⁺.

Example 6

(4-(4-Chloro-2-methoxyphenyl)-2-phenylpyrimidin-5-yl)methanamine, TFAsalt was prepared by the methods described in Example 1 using2-methoxy-4-chlorobenzoyl chloride for Step 1 and benzamidinehydrochloride for Step 3.

¹H NMR (400 MHz, CD₃OD) 8.96 (s, 1H), 8.44 (dd, J=1.76, 7.92 Hz, 2H),7.51 (m, 4H), 7.27 (d, J=1.76 Hz, 1H), 7.22 (dd, J=1.80, 7.75 Hz, 1H),4.08 (s, 2H), 3.88 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=5.49 min, 98%homogeneity index.

HRMS: Anal. Calcd. for C₁₈H₁₇ClN₃O 326.1060 found: 326.1048 (M+H)⁺.

Example 7

(4-(2,4-Dimethylphenyl)-2-phenylpyrimidin-5-yl)methanamine, TFA salt wasprepared by the methods described in Example 1 using 2,4-dimethylbenzoylchloride for Step 1 and benzamidine hydrochloride for Step 3.

¹H NMR (400 MHz, CD₃OD) 9.14 (s, 1H), 8.43 (dd, J=1.75, 7.60 Hz, 2H),7.53 (m, 3H), 7.26 (m, 3H), 4.13 (s, 2H), 2.42 (s, 3H), 2.14 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=5.39 min, 99%homogeneity index.

HRMS: Anal. Calcd. for C₁₉H₂₀N₃ 290.1657 found: 290.1643 (M+H)⁺.

Example 8

Example 8 Step 1. Methyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate

To a stirred solution of methyl acetoacetate (345 mg, 2.97 mmol) and2,4-dichlorobenzaldehyde (500 mg, 2.86 mmol) in 2-propanol (5 mL) wasadded AcOH (7 mg, 0.11 mmol) and dimethylamine (0.06 mL, 2M in THF, 0.11mmol). The reaction was heated to 40° C. for 4 hrs followed by coolingto ambient temperature for 15 hrs. The reaction was concentrated andpurified by flash chromatography (silica gel, 30% EtOAc/hexane) to givemethyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate as a mixture of twoisomers (colorless oil, 610 mg, 78%).

¹H NMR (400 MHz, CDCl₃) Fast eluting isomer: 7.86 (s, 1H), 7.45 (d,J=2.2 Hz, 1H), 7.25 (d, J=6.8 Hz, 1H), 7.21 (dd, J=2.2, 7.0 Hz, 1H),3.85 (s, 3H), 2.24 (s, 3H). Slow eluting isomer: 7.78 (s, 1H), 7.45 (d,J=2.2 Hz, 1H), 7.34 (d, J=7.0 Hz, 1H), 7.25 (dd, J=2.2, 7.0 Hz, 1H),3.73 (s, 3H), 2.44 (s, 3H).

Example 8 Step 2. Methyl4-(2,4-dichlorophenyl)-6-methyl-2-phenyl-1,4-dihydropyrimidine-5-carboxylate

To a stirred solution of methyl2-(2,4-dichlorobenzylidene)-3-oxobutanoate (480 mg, 1.8 mmol) andbenzamidine HCl salt (275 mg, 1.8 mmol) in DMF (6 mL) was added NaOAc(144 mg, 1.8 mmol). The reaction was heated to 60° C. for 3 days and wasquenched by 1N HCl (10 mL). The reaction was diluted with EtOAc (10 mL)and the organic layer was washed with 1N HCl, saturated NH4Cl solution(10 mL) and brine (10 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure to give the crude product as a yellow oil (600mg). The crude reaction product was moved onto next step without furtherpurification.

LCMS: Anal. Calcd. for C₁₉H₁₆C₁₂N₂O₂ 374.06 found: 375.00 (M+H)⁺.

Example 8 Step 3. Methyl4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate

To a stirred solution of methyl4-(2,4-dichlorophenyl)-6-methyl-2-phenyl-1,4-dihydropyrimidine-5-carboxylate(600 mg, 1.76 mmol) in PhCH₃ (6 mL) was added MnO₂ (227 mg, 2.64 mmol)and the reaction was heated to 95° C. for 14 hrs. The reaction wasfiltered through a pad of celite, concentrated under reduced pressure,and purified by flash chromatography (silica gel, 30% EtOAc/hexane) togive methyl4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate (150mg, 23% for 2 steps) and4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylic acid(100 mg, 15% for 2 steps).

¹H NMR (400 MHz, CDCl₃) 8.44 (dd, J=1.3, 7.6 Hz, 2H), 7.38-7.47 (m, 4H),7.30 (d, J=1.3 Hz, 2H), 3.62 (s, 3H), 2.71 (s, 3H).

For acid ¹H NMR (400 MHz, CDCl₃/CD₃OD) 8.04 (dd, J=1.3, 7.9 Hz, 2H),7.41-7.57 (m, 3H), 7.37 (s, 1H), 7.26 (d, J=7.9 Hz, 2H), 2.48 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=3.63 min, 90%homogeneity index.

Example 8 Step 4.(4-(2,4-Dichlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)methanol

To a stirred solution of4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate (75 mg,0.2 mmol) in THF (6 mL) was added DIBAL (0.4 mL, 1.5 M in PhCH₃, 0.6mmol). The reaction was kept for 1 hr and was quenched by saturatedaqueous potassium sodium tartrate solution (5 mL). The reaction wasdiluted with EtOAc (10 mL) and the organic layer was washed with 1N NaOH(10 mL), saturated Na₂CO₃ solution (10 mL) and brine (10 mL), dried(MgSO₄), filtered and concentrated under reduced pressure to give thecrude product as a white solid (75 mg). The crude reaction product wasmoved onto next step without further purification.

¹H NMR (400 MHz, CDCl₃) 8.36 (dd, J=1.2, 7.5 Hz, 2H), 7.47 (s, 1H), 7.39(m, 3H), 7.30 (dd, J=2.6, 8.0 Hz, 2H), 4.52 (br s, 1H), 4.42 (br s, 1H),2.72 (s, 3H).

Example 8 Step 5.4-(2,4-Dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde

To a stirred solution of(4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)methanol (75 mg,0.2 mmol) in CH₂Cl₂ (6 mL) was added Dess-Martin periodinane (102 mg,0.24 mmol). The reaction was kept for 2 hrs and was diluted with EtOAc(10 mL). The organic layer was washed with saturated NaHCO₃ solution (10mL), and brine (10 mL), dried (MgSO₄), filtered and concentrated underreduced pressure to give the crude product as a white solid (75 mg). Thecrude product was purified by flash chromatography (silica gel, 30%EtOAc/hexane) to give4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde (65mg, 91% for 2 steps) as a white solid.

¹H NMR (400 MHz, CDCl₃) 9.90 (s, 1H), 8.47 (dd, J=1.8, 8.4 Hz, 2H),7.37-7.49 (m, 6H), 2.88 (s, 3H).

Example 8 Step 5.4-(2,4-Dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde oxime

To a stirred solution of4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde (24mg, 0.07 mmol) in EtOH (4 mL) was added NH₂OH.HCl (10 mg, 0.14 mmol) andEt₃N (50 μL). The reaction was heated to 70° C. for 3 hrs and wasconcentrated under reduced pressure. The residue was dissolved in EtOAc(10 mL) and the organic layer was washed by saturated NH₄Cl solution (10mL) and brine, dried (MgSO₄), filtered and concentrated under reducedpressure to give the crude product as a white solid (24 mg). The crudereaction product was moved onto next step without further purification.

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.1% trifluoroacetic acid,B=10% water, 90% methanol, 0.1% trifluoroacetic acid, RT=4.09 min, 95%homogeneity index.

LCMS: Anal. Calcd. for C₁₈H₁₃C₁₂N₃O 357.04 found: 357.97 (M+H)⁺.

Example 8 Step 5.(4-(2,4-Dichlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)methanamine

To a stirred solution4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carbaldehyde oxime(24 mg, 0.07 mmol) in EtOH (4 mL) was added Zn (14 mg, 0.21 mmol),NH₄OAc (16 mg, 0.21 mmol) and NH₄OH (30 μL, 28% in H₂O, 0.21 mmol). Thereaction was heated to 78° C. for 15 hrs. Additional 3 eqs of Zn,NH₄OAc, NH₄OH were added and after 3 hrs, the reaction was concentratedunder reduced pressure and diluted with EtOAc (10 mL). The organic layerwas washed by saturated NaHCO₃ solution (10 mL) and brine, dried(MgSO₄), filtered and concentrated under reduced pressure to give thecrude product. The crude product was purified by reverse-phasepreparative HPLC to provide(4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)methanamine, TFAsalt (20 mg, 63% for 2 steps) as a light yellow solid.

¹H NMR (400 MHz, CD₃OD) 8.44 (dd, J=1.6, 8.4 Hz, 2H), 7.72 (d, J=1.3 Hz,1H), 7.46-7.62 (m, 5H), 4.27 (d, J=14.5 Hz, 1H), 4.00 (d, J=14.5 Hz,1H), 2.82 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=2.83 min, 99%homogeneity index.

LCMS: Anal. Calcd. for C₁₈H₁₅C₁₂N₃ 343.06 found: 343.99 (M+H)⁺.

HRMS: Anal. Calcd. for C₁₈H₁₆C₁₂N₃ 344.0721 found: 344.0728 (M+H)⁺.

Example 9

Example 9 Step 1. (4-Chloro-2-phenylpyrimidin-5-yl)methanol

To a stirred solution of methyl 4-chloro-2-phenylpyrimidine-5-carboxylate (300 mg, 1.14 mmol) in CH₂Cl₂ (15 mL) at -78° C. wasadded DIBAL (1.5 M in PhCH₃, 1.5 mL, 2.28 mmol). The reaction was keptfor 2 hrs and was quenched by saturated aqueous potassium sodiumtartrate solution (10 mL). The reaction was diluted with EtOAc (15 mL)and the organic layer was washed with 1 N NaOH (10 mL), saturated Na₂CO₃solution (10 mL) and brine (10 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure to give the crude product as ayellow solid (242 mg). The crude reaction product was moved onto nextstep without further purification.

¹H NMR (400 MHz, CD₃OD) 8.73 (s, 1H), 8.30 (d, J=1.3, 6.2 Hz, 2H),7.38-7.41 (m, 3H), 4.64 (s, 2H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=6.17 min, 95%homogeneity index.

LCMS: Anal. Calcd. for C₁₁H₉ClN₂O 220.04 found: 221.04 (M+H)⁺.

Example 9 Step 2. 4-Chloro-2-phenylpyrimidine-5-carbaldehyde

To a stirred (4-chloro-2-phenylpyrimidin-5-yl)methanol (242 mg, 1.10mmol) in CH₂Cl₂ (11 mL) was added Dess-Martin periodinane (553 mg, 1.43mmol). The reaction was kept for 2 hrs and was diluted with EtOAc (10mL).The organic layer was washed with saturated NaHCO₃ solution (10 mL),and brine (10 mL), dried (MgSO₄), filtered and concentrated underreduced pressure to give the crude product as a white solid (250 mg).The crude product was purified by flash chromatography (silica gel, 20%EtOAc/hexane) to give 4-chloro-2-phenylpyrimidine-5-carbaldehyde (205mg, 82% for 2 steps) as a white solid.

¹H NMR (400 MHz, CDCl₃) 10.43 (s, 1H), 9.12 (s, 1H), 8.51 (dd, J=1.4,6.2 Hz, 2H), 7.48-7.59 (m, 3H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=6.60 min, 99%homogeneity index.

LCMS: Anal. Calcd. for C₁₁H₇ClN₂O 218.02 found: 219.06 (M+H)⁺.

Example 9 Step 3.4-(4-Chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde

To a stirred solution of 4-chloro-2-phenylpyrimidine-5-carbaldehyde (50mg, 0.23 mmol) and 4-chloro-o-toluene boronic acid (48 mg, 0.29 mmol) indioxane (1 mL) and H₂O (0.5 mL) was added Pd(PPh₃)₄ (26.5 mg, 0.02mmol), K₂CO₃ (126.5 mg, 0.92 mmol). The reaction was heated to 85° C.for 6 hrs. After concentration under reduced pressure, the residue wasdiluted with EtOAc (10 mL) and the organic layer was washed withsaturated NH₄Cl solution (10 mL), and brine (10 mL), dried (MgSO₄),filtered and concentrated under reduced pressure to give the crudeproduct (70 mg). The crude product was purified by flash chromatography(silica gel, 20% EtOAc/hexane) to give4-(4-chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde (63 mg,75%) as a white solid.

¹H NMR (400 MHz, CDCl₃) 9.82 (s, 1H), 9.26 (s, 1H), 8.48 (dd, J=1.8, 8.4Hz, 2H), 7.41-7.52 (m, 3H), 7.12-7.37 (m, 3H), 2.26 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=7.84 min, 90%homogeneity index.

LCMS: Anal. Calcd. for C₁₈H₁₃ClN₂O 308.07 found: 309.06 (M+H)⁺.

Example 9 Step 4.4-(4-Chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde oxime

To a stirred solution of4-(4-chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde (63 mg,0.20 mmol) in EtOH (4 mL) was added NH₂OH.HCl (28.3 mg, 0.41 mmol) andpyridine (430 μL). The reaction was heated to 70° C. for 3 hrs and wasconcentrated under reduced pressure. The residue was dissolved in EtOAc(10 mL) and the organic layer was washed by saturated NH4Cl solution (10mL) and brine, dried (MgSO₄), filtered and concentrated under reducedpressure to give the crude product as a light yellow foam (69 mg). Thecrude reaction product was moved onto next step without furtherpurification.

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=8.26 min, 95%homogeneity index.

LCMS: Anal. Calcd. for C₁₈H₁₄ClN₃O 323.08 found: 324.06 (M+H)⁺.

Example 9 Step 5.(4-(4-Chloro-2-methylphenyl)-2-phenylpyrimidin-5-yl)methanamine

To a stirred solution(4-(4-chloro-2-methylphenyl)-2-phenylpyrimidin-5-yl)methanamine (69 mg,0.21 mmol) in EtOH (5 mL) was added Zn (28 mg, 0.43 mmol), NH₄OAc (33mg, 0.43 mmol) and NH₄OH (58 μL, 28% in H₂O, 0.43 mmol). The reactionwas heated to 78° C. for 10 hrs. Additional 2 eqs of Zn, NH₄OAc, NH₄OHwere added and after 3 hrs, the reaction was concentrated under reducedpressure and diluted with EtOAc (10 mL). The organic layer was washed bysaturated NaHCO₃ solution solution (10 mL) and brine, dried (MgSO₄),filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by reverse-phase preparativeHPLC to provide(4-(4-chloro-2-methylphenyl)-2-phenylpyrimidin-5-yl)methanamine, TFAsalt (27 mg, 40% for 2 steps) as a white solid.

¹H NMR (400 MHz, CD₃OD) 9.04 (s, 1H), 8.44 (dd, J=1.3, 8.3 Hz, 2H),7.44-7.54 (m, 4H), 7.38 (dd, J=1.8, 6.2 Hz, 1H), 7.9 (d, J=7.9 Hz, 1H),4.07 (s, 2H), 2.21 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×75 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=5.52 min, 99%homogeneity index.

LCMS: Anal. Calcd. for C₁₈H₁₆ClN₃ 309.10 found: 310.07 (M+H)⁺.

HRMS: Anal. Calcd. for C₁₈H₁₇ClN₃ 310.1111 found: 310.1101 (M+H)⁺.

Example 10

Example 10 Step 1. Diethyl 2-(2,4-dichlorobenzylidene)malonate

To a stirred solution of diethyl malonate (0.92 g, 5.71 mmol) in toluene(10 mL) was added 2,4-dichlorobenzaldehyde (1 g, 5.71 mmol), piperidine(23 μL, 0.23 mmol), acetic acid (13 μL, 0.23 mmol) and molecular sieves(3 Å). The reaction was heated to 70° C. for 2 days and was concentratedunder reduced pressure. The residue was filtered through a pad of silicaflushing with EtOAc/hexane (1:1) solution. The filtrate was concentratedto give diethyl 2-(2,4-dichlorobenzylidene)malonate (1.83 g, 97%) as ayellow oil.

¹H NMR (400 MHz, CDCl₃) 7.94 (s, 1H), 7.46 (d, J=2.2 Hz, 1H), 7.40 (d,J=7.0 Hz, 1H), 7.22 (dd, J=2.2, 7.0 Hz, 1H), 4.20-4.37 (m, 6H), 1.34 (t,J=J=7.0 Hz, 4.5 H), 1.24 (t, J=7.0 Hz, 4.5 H).

Example 10 Step 2. Ethyl4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate

A solution of diethyl 2-(2,4-dichlorobenzylidene)malonate (300 mg, 0.91mmol) and benzamidine (134 mg, 0.91 mmol) in EtOH (3 mL) was heated to60° C. for 2 hrs. The reaction was concentrated under reduced pressure.The resulting residue was dissolved in CH₂Cl₂ (4 mL) and DDQ (238 mg,1.05 mmol) was added. After 1 hr, The reaction was diluted withcyclohexane/EtOAc solution (4:1, 100 mL) and the organic layer wasextracted with saturated NaHCO₃ solution (2×60 mL), brine (50 mL). Theorganic layer dried (MgSO₄), filtered and concentrated under reducedpressure to give ethyl4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate(372 mg, 100%) as a yellow solid. This product was moved onto next stepwithout further purification.

¹H NMR (400 MHz, CDCl₃) 8.32 (d, J=6.6 Hz, 2H), 7.32-7.63 (m, 6H), 4.16(q, J=7.0Hz, 2H), 1.16 (t, J=7.0Hz, 3H).

Example 10 Step 3. Ethyl4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate

To a stirred solution of ethyl4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate(372 mg, 0.91 mmol) in doixane (6 mL) was added POCl₃ (0.4 mL, 4.55mmol) and N,N-dimethylaniline (11.5 μL, 0.09 mmol). After 4 hrs at 70°C., the reaction was concentrated under reduced pressure and dilutedwith EtOAc (100 mL). The organic layer was extracted with saturatedNaHCO₃ solution (2×60 mL), brine (50 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude reaction product waspurified by flash chromatography (silica gel, 30% EtOAc/hexane) to giveethyl 4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate(360 mg, 97% for 3 steps) as a clear oil.

¹H NMR (400 MHz, CDCl₃) 8.48 (d, J=6.6 Hz, 2H), 7.47-7.58 (m, 6H), 4.21(q, J=7.0 Hz, 2H), 1.12 (t, J=7.0 Hz, 3H).

Example 10 Step 4. Ethyl4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidine-5-carboxylate

A solution of ethyl4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate (30 mg,0.07 mmol) and phenyl boronic acid (14 mg, 0.11 mmol) in toluene (3 mL)was degassed with argon for 15 minutes. To this solution was addedPd(PPh₃)₄ (9 mg, 0.007 mmol), Na₂CO₃ (23 mg, 0.22 mmol) and the reactionwas heated to reflux for 3 days. The reaction was diluted with EtOAc (20mL) and extracted with saturated NH₄Cl solution (2×20 mL), brine (20mL). The organic layer was dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude reaction product was purified by flashchromatography (silica gel, 20% EtOAc/hexane) to give ethyl4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidine-5-carboxylate (14 mg,42%).

¹H NMR (400 MHz, CDCl₃) 8.58 (dd, J=1.3, 8.4 Hz, 2H), 7.80 (d, J=8.0 Hz,2H), 7.46-7.57 (m, 7H), 7.36-7.43 (m, 2H), 4.00 (q, J=7.0 Hz, 2H), 0.91(t, J=7.0 Hz, 3H).

Example 10 Steps 5-8.(4-(2,4-Dichlorophenyl)-2,6-diphenylpyrimidin-5-yl)methanamine

To a stirred solution of ethyl4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidine-5-carboxylate (14 mg, 0.03mmol) in THF (2 mL) was added DIBAL-H (0.05 mL, 0.08 mmol). The reactionwas kept at ambient temperature for 1 hr and then 50° C. for 1 hr andwas quenched by sodium potassium tartrate solution (30%, 10 mL).). Thereaction was diluted with EtOAc (15 mL) and the organic layer was washedwith 1N NaOH (10 mL), saturated Na₂CO₃ solution (10 mL) and brine (10mL), dried (MgSO₄), filtered and concentrated under reduced pressure.The crude reaction product was purified by flash chromatography (silicagel, 20% EtOAc/hexane) to give the alcohol (10 mg, 79%).

To a stirred solution of alcohol (10 mg, 0.025 mmol) in CH₂Cl₂ (2 mL)was added MsCl (4 μL, 0.049 mmol) and Et₃N (17 μL, 0.12 mmol). Thereaction was kept at ambient temperature for 16 hrs and was quenched byaddition of H₂O (5 mL). The organic layer was extracted with H₂O andbrine, dried (MgSO₄), filtered and concentrated under reduced pressureto afford the desired mesylate. The crude reaction product was dissolvein DMF (2 mL) and NaN₃ (2.5 mg, 0.037 mmol) was added. The reaction washeated to 50° C. for 1 hr and was quenched by H₂O (5 mL). The aqueouslayer was extracted with EtOAc (2×10 mL) and the combined organic layerswere washed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure to give the desired azide. The azide was dissolved inTHF (1 mL) and H₂O (0.2 mL) and PPh₃ (polymer supported, 3 mmol/g, 16mg, 0.049 mmol) was added. The reaction was heated to 50° C. for 1 hrand filtered to remove polymer support. The filtrated was concentratedunder reduced pressure and purified by reverse-phase preparative HPLC toprovide (4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidin-5-yl)methanamine,TFA salt (5 mg, 50% for 3 steps) as a white solid.

¹H NMR (400 MHz, CD₃OD) 8.49 (dd, J=1.8, 8.4 Hz, 2H), 7.74-7.82 (m, 3H),7.60-7.70 (m, 5H), 7.47-7.59 (m, 3H), 4.37 (d, J=14.5 Hz, 1H), 4.13 (d,J=14.5 Hz, 1H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=3.52 min, 99% homogeneity index.

LCMS: Anal. Calcd. for C₂₃H₁₇C₁₂N₃ 405.08 found: 406.19 (M+H)⁺.

HRMS: Anal. Calcd. for C₂₃H₁₈C₁₂N₃ 406.0878 found: 406.0895 (M+H)⁺.

Example 11

(4-(2,4-Dichlorophenyl)-6-ethyl-2-phenylpyrimidin-5-yl)methanamine, TFAsalt was prepared by the methods described in Example 8, using methyl3-oxopentanoate for Step 1.

¹H NMR (400 MHz, CD₃OD) 8.38 (dd, J=1.76, 6.16Hz, 1H), 7.64 (d, J=1.76Hz, 1H), 7.37-7.53 (m, 6H), 4.17 (d, J=14.5 Hz, 1H), 3.89 (d, J=15.5 Hz,1H), 2.99 (m, 2H), 1.43 (t, J=7.48 Hz, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=5.84 min, 100%homogeneity index.

LCMS: Anal. Calcd. for C₁₉H₁₇C₁₂N₃ 357.08 found: 358.06 (M+H)⁺.

LCMS: Anal. Calcd. for C₁₉H₁₈C₁₂N₃ 358.0878 found: 358.00884 (M+H)⁺.

EXAMPLE 12

(4-(2,4-Dichlorophenyl)-2,6-dimethyl-pyrimidin-5-yl)methanamine, TFAsalt was prepared by the methods described in Example 8, usingacetamidine, hydrochloride for Step 2.

¹H NMR (400 MHz, CD₃OD) 7.60 (d, J=1.96 Hz, 1H), 7.45 (dd, J=1.96, 8.32Hz, 1H), 7.36 (d, J=8.32 Hz, 1H), 4.11 (d, J=14.96 Hz, 1H), 3.83 (d,J=14.96 Hz, 1H), 2.61 (s, 3H), 2.60 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 8 minutes, 2minutes hold time, A=90% water, 10% methanol, 0.2% phosphoric acid,B=10% water, 90% methanol, 0.2% phosphoric acid, RT=3.10 min, 100%homogeneity index.

LCMS: Anal. Calcd. for C₁₃H₁₃C₁₂N₃ 281.05 found: 282.19 (M+H)⁺.

HRMS: Anal. Calcd. for C₁₃H₁₄Cl₂N₃ 282.0565 found: 282.0569 (M+H)⁺.

EXAMPLE 13

Example 13 Step 1. Methyl2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate

To a stirred solution of methyl2-(2,4-dichlorobenzylidene)-3-oxobutanoate from Example 8, Step 1 (60mg, 0.22 mmol) and benzylthiourea HCl salt (44 mg, 0.22 mmol) in DMF (2mL) was added molecular sieves (3 Å). The reaction was heated to 90° C.for 16 hrs and was diluted with EtOAc (15 mL) and filtered to removemolecular sieves. The organic layer was extracted with H₂O (2×10 mL),brine, dried (MgSO₄), filtered and concentrated under reduced pressureto afford the desired methyl2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate.The crude reaction product (>95% purity) was moved onto next stepwithout further purification.

Example 13 Step 2. Methyl2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate

The crude methyl2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate(0.22 mmol) from Step 1 was dissolved in CH₂Cl₂ (2 mL) and DDQ (50 mg,0.22 mmol) was added. After 1 hr, The reaction was diluted withcyclohexane/EtOAc solution (4:1, 10 mL) and the organic layer wasextracted with saturated NaHCO₃ solution (2×6 mL), brine (5 mL). Theorganic layer dried (MgSO₄), filtered and concentrated under reducedpressure to give methyl2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate.The crude reaction product (>95% purity) was moved onto next stepwithout further purification.

¹H NMR (400 MHz, CDCl₃) 7.45 (d, J=1.3 Hz, 1H), 7.41 (d, J=6.2 Hz, 1H),7.20-7.37 (m, 6H), 4.41 (s, 2H), 3.63 (s, 3H), 2.66 (s, 3H).

Example 13 Step 3. Methyl2-(benzylsulfonyl)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate

To crude methyl2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate(0.22 mmol) from Step 2 in CH₂Cl₂ (3 mL) was added mCPBA (105 mg, 0.55mmol). After 16 hrs, the reaction was concentrated under reducedpressure and diluted with EtOAc (10 mL). The organic layer was extractedwith saturated NaHCO₃ solution (2×6 mL), brine (5 mL), dried (MgSO₄),filtered and concentrated under reduced pressure. The crude reactionproduct was purified by flash chromatography (silica gel, 20%EtOAc/hexane) to give methyl2-(benzylsulfonyl)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate(80 mg, 80% for 3 steps) as a clear oil.

¹H NMR (400 MHz, CDCl₃) 7.51 (s, 1H), 7.26-7.42 (m, 7H), 4.80 (s, 2H),3.72 (s, 3H), 2.79 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=3.48 min.

LCMS: Anal. Calcd. for C₂₀H₁₆C₁₂N₂O₄S 450.02 found: 451.15 (M+H)⁺.

Example 13 Step 4. Methyl4-(2,4-dichlorophenyl)-6-methyl-2-thiomorpholinopyrimidine-5-carboxylate

To a stirred solution of methyl2-(benzylsulfonyl)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate(17 mg, 0.037 mmol) in dioxane (2 mL) was added thiomorpholine (4.5 mL,0.045 mmol). After at 40° C. for 1 hr, the reaction was concentratedunder reduced pressure and diluted with EtOAc (10 mL). The organic layerwas extracted with saturated NaHCO₃ solution (2×6 mL), brine (5 mL),dried (MgSO₄), filtered and concentrated under reduced pressure to givemethyl4-(2,4-dichlorophenyl)-6-methyl-2-thiomorpholinopyrimidine-5-carboxylate(15 mg, 100%). The crude reaction product (>98% purity) was moved ontonext step without further purification.

¹H NMR (400 MHz, CDCl₃) 7.43 (d, J=1.8 hz, 1H), 7.31 (dd, J=1.8, 8.4 Hz,1H), 7.22 (d, J=8.4 Hz, 1H), 4.21 (m, 4H), 3.55 (s, 3H), 2.66 (m, 4H),2.58 (s, 3H).

Example 13 Step 5-8.(4-(2,4-Dichlorophenyl)-6-methyl-2-thiomorpholinopyrimidin-5-yl)methanamine,TFA Salt

(4-(2,4-Dichlorophenyl)-6-methyl-2-thiomorpholinopyrimidin-5-yl)methanamine,TFA salt was prepared by the methods described in Example 10, Step 5-8.

¹H NMR (400 MHz, CD₃OD) 7.67 (d, J=1.2 Hz, 1H), 7.52 (dd, J=1.2, 7.6 Hz,1H), 7.40 (d, J=7.6 Hz, 1H), 4.17 (m, 4H), 4.06 (d, J=15.2 Hz, 1H), 3.78(d, J=15.2 Hz, 1H), 2.63 (m, 4H), 2.53 (s, 3H).

HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1minutes hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=3.37 min, 95% homogeneity index.

LCMS: Anal. Calcd. for C₁₆H₁₈C₁₂N₄S 368.06 found: 369.18 (M+H)⁺.

1. A compound of formula (I)

wherein: n=1 or 2; R is a substitutent selected from the groupconsisting of hydrogen (H), halogen, cyano (CN), CF₃, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl,alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl,wherein any such substituent may optionally be substituted throughavailable carbon atoms with 1, 2, 3, 4 or 5 groups selected fromhydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino,cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,cyano, amino, substituted amino, alkylamino, dialkylamino, thiol,alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl; Bis selected from the group consisting of a bond, oxygen (O), nitrogen(N) and S(O)_(m); m is 0, 1 or 2; X is a substitutent selected from thegroup consisting of hydrogen (H), alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl,arylalkylthioalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, wherein anysuch substituent may optionally be substituted through available carbonatoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl,polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino,alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino,alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl,sulfonamido and sulfonyl; B—X taken together can be a halogen; and Y isaryl, optionally substituted with 1, 2, 3, 4 or 5 groups selected fromhydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino,cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,cyano, amino, substituted amino, alkylamino, dialkylamino, thiol,alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino,alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;including pharmaceutically acceptable salts thereof, and prodrug estersthereof, and all stereoisomers thereof.
 2. The compound as defined inclaim 1 wherein n is
 1. 3. The compound as defined in claim 1 selectedfrom


4. A pharmaceutical composition comprising a compound as defined inclaim 1 and a pharmaceutically acceptable carrier therefore.
 5. Apharmaceutical combination comprising a compound of formula I as definedin claim 1 and at least one therapeutic agent selected from the groupconsisting of an antidiabetic agent, an anti-obesity agent, aanti-hypertensive agent, an anti-atherosclerotic agent and alipid-lowering agent.
 6. The pharmaceutical combination as defined inclaim 5 wherein the therapeutic agent is an antidiabetic agent.
 7. Thecombination as defined in claim 6 wherein the antidiabetic agent is atleast one agent selected from the group consisting of a biguanide, asulfonyl urea, a glucosidase inhibitor, a PPAR gamma agonist, a PPARalpha/gamma dual agonist, an aP2 inhibitor, a SGLT2 inhibitor, aninsulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and ameglitinide.
 8. The combination as defined in claim 7 wherein theantidiabetic agent is at least one agent selected from the groupconsisting of metformin, glyburide, glimepiride, glipyride, glipizide,chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone,troglitazone, rosiglitazone, insulin, isaglitazone, repaglinide andnateglinide.
 9. The combination as defined in claim 6 wherein thecompound of formula I is present in a weight ratio to the antidiabeticagent in the range of about 0.01 to about 300:1.
 10. The combination asdefined in claim 5 wherein the anti-obesity agent is at least one agentselected from the group consisting of a beta 3 adrenergic agonist, alipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, athyroid receptor beta compound and an anorectic agent.
 11. Thecombination as defined in claim 10 wherein the anti-obesity agent is atleast one agent selected from the group consisting of orlistat,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.
 12. The combination as defined inclaim 5 wherein the lipid lowering agent is at least one agent selectedfrom the group consisting of an MTP inhibitor, cholesterol estertransfer protein, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, or an ACAT inhibitor.
 13. Thecombination as defined in claim 12 wherein the lipid lowering agent isat least one agent selected from the group consisting of pravastatin,lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate andavasimibe.
 14. The combination as defined in claim 5 wherein thecompound of formula I is present in a weight ratio to the lipid-loweringagent in the range of about 0.01 to about 100:1.
 15. A method fortreating or delaying the progression or onset of diabetes, diabeticretinopathy, diabetic neuropathy, diabetic nephropathy, wound healing,insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X,diabetic complications, elevated blood levels of free fatty acids orglycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosisor hypertension, which comprises administering to a mammalian species inneed of treatment a therapeutically effective amount of a compound asdefined in claim
 1. 16. A method according to claim 15 furthercomprising administering, concurrently or sequentially, atherapeutically effective amount of at least one additional therapeuticagent selected from the group consisting of an antidiabetic agent, ananti-obesity agent, a anti-hypertensive agent, an anti-atheroscleroticagent, an agent for inhibiting allograft rejection in transplantationand a lipid-lowering agent.
 17. A pharmaceutical composition thatinhibits DPP-IV containing a compound as defined in claim
 1. 18. Amethod of inhibiting DPP-W comprising administering a pharmaceuticalcomposition comprising a compound as defined in claim 1.